Abstract
Polymerase basic protein 1 (PB1), the catalytic core of the influenza A virus RNA polymerase complex, is essential for viral transcription and replication. Dendritic cells (DCs) possess important antigen presenting ability and a crucial role in recognizing and clearing virus. MicroRNA (miRNA) influence the development of DCs and their ability to present antigens as well as the ability of avian influenza virus (AIV) to infect host cells and replicate. Here, we studied the molecular mechanism underlying the miRNA-mediated regulation of immune function in mouse DCs. We first screened for and verified the induction of miRNAs in DCs after PB1 transfection. Results showed that the viral protein PB1 down-regulated the expression of miR375, miR146, miR339, and miR679 in DCs, consistent with the results of H9N2 virus treatment; however, the expression of miR222 and miR499, also reduced in the presence of PB1, was in contrast to the results of H9N2 virus treatment. Our results suggest that PB1 enhanced the ability of DCs to present antigens, activate lymphocytes, and secrete cytokines, while miR375 over-expression repressed activation of DC maturation. Nevertheless, PB1 could not promote DC maturation once miR375 was inhibited. Finally, we revealed that PB1 inhibited the P-Jnk/Jnk signaling pathway, but activated the p-Erk/Erk signaling pathway. While inhibition of miR375 -activated the p-Erk/Erk and p-p38/p38 signaling pathway, but repressed the P-Jnk/Jnk signaling pathway. Taken together, results of our studies shed new light on the roles and mechanisms of PB1 and miR375 in regulating DC function and suggest new strategies for combating AIV.
Highlights
The influenza virus contains eight segments of a single-stranded RNA genome with negative polarity
Since miRNA have the ability to modulate Dendritic cells (DCs) function, and our previous research work demonstrated that H9N2 avian influenza virus (AIV) significantly influenced miRNA expression of DCs, the purpose of our study was to investigate the role miRNA play in regulating the immune response of DCs to PB1 stimulation
The expression of selected miRNAs was examined by reverse transcription quantitative real-time PCR (RT-qPCR)
Summary
The influenza virus contains eight segments of a single-stranded RNA genome with negative polarity. The H9N2 subtype avian influenza virus (AIV), classified as a low pathogenic AIV, has high genetic variability and has shown both increases in virulence and ability to cross the host barrier (Peiris et al, 1999; Jin et al, 2014; Shaib et al, 2014; Zhou et al, 2014). The virus polymerase complex of H9N2 AIV, consisting of the polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2) and polymerase acidic protein (PA) subunits, has been reported to charge for catalyzing both viral RNA genome replication and transcription. Previous studies have shown that PB1 serves as a core subunit to incorporate PA and PB2 into the polymerase complex by directly interacting with PA and PB2 (Hemerka et al, 2009). Studies reveal that PB1 interacted with PA was an attractive target for drug treatment (Massari et al, 2016; Swale et al, 2016)
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